The compound 2-N(3-O-(propan 2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide is disclosed in U.S. Pat. No. 7,754,771, and has proven to be efficient in the treatment of HIV-1 infection. This compound has been further disclosed for use in the treatment or prophylaxis of pain and inflammation in WO 2009/1099850, WO 2011/030105 and US 2011/0086910. Previous disclosures on this compound have related to the racemate containing all four enantiomers and diastereomers, namely (S,S), (S,R), (R,R) and (R,S). The racemate containing the S enantiomers at the chiral position adjacent to the amide, were disclosed as a particularly advantageous embodiment.
Pain is a multifaceted or multidimensional, experiential response to a variety of stimulus conditions. Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.
Pain can be acute or chronic. Acute pain is usually caused by soft tissue damage, infection and/or inflammation among other causes. Chronic pain may have no apparent cause or may be caused by a developing illness or imbalance. Chronic pain is defined as the disease of pain; its origin, duration, intensity and specific symptoms may vary. Moreover, chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Nociceptive pain has been traditionally managed by administering non-opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Neuropathic pain, a debilitating chronic pain following nerve damage, is characterized by its chronic nature, hyperalgesia, or abnormal pain hypersensitivity to innocuous stimuli (tactile allodynia). Hyperalgesia is an exaggerated response to a painful stimulus. Allodynia is the perception of normal stimuli as painful (examples include the touch of clothing, warm or cool air, etc.). Neuropathic pain can be a sequel to nerve damage in an extremity such as an arm, or more often, a leg. Precipitating events can include trauma or amputations (e.g., phantom limb pain). Neuropathic pain can occur due to an adverse effect of drug therapies, e.g., vincristine or paclitaxel (Taxol™), or can occur as a component of disease pathologies, such as diabetes type 1 or type 2, shingles, HIV-1 infections, etc. Typically, neuropathic pain does not respond to opiates or non-steroidal anti-inflammatory drugs such as aspirin. Current suggested medicaments to Neuropathic pain include anti-epileptics (e.g., gabapentin, carbamazepine, valproic acid, topiramate, phenyloin), NMDA antagonists (e.g., ketamine, dextromethorphan), topical lidocaine (for post-herpetic neuralgia), and tricyclic antidepressants (e.g., fluoxetine, sertraline and amitriptyline).
The underlying mechanisms of neuropathic pain are still to be determined. However, it has been recently suggested that Lyn tyrosine kinase, a member of the Src family kinases (SFKs) plays an important role in the pathogenesis of neuropathic pain. Lyn expression in the spinal cord was highly restricted to microglia, and its level was increased after nerve injury. It has been shown that mice lacking Lyn exhibit a striking reduction in their ability to tactile allodynia after nerve injury. It was concluded that neuropathic pain may be linked to up-regulation of Lyn tyrosine kinase. (See Tsuda et al., Glia, 2008, 56:50-8).
The currently available treatments for neuropathic pain have only low to moderate efficacy, and many patients are left without significant pain relief. The lack of adequate pain relief for millions of people with neuropathic pain, as well as for those with other types of pain, represents a great unmet medical need, this invention addresses that need.